Drotrecogin alpha: a rational approach to the treatment of submassive pulmonary embolism?

Combining therapeutic doses of low-molecular-weight heparins and increasing doses of recombinant activated protein C - Drotrecogin alpha (activated), or DAA - is of theoretical interest with regard to the control of coagulation activation. The study by Dempfle and colleagues presents new data showing that endogenous activated protein C levels do not increase in nonseptic patients with pulmonary embolism. However, the results of the addition of these two treatments are puzzling, leaving unresolved the questionable clinical relevance of this combination and the possible increase in bleeding risk.

In this issue of Critical Care, Dempfl e and colleagues [1] present an original double-blind study assessing the biological eff ect of the combination of enoxaparin and Drotrecogin alpha (activated) (DAA) (recombinant human activated protein C) for the treatment of acute sub massive pulmonary embolism (PE). Th e authors demon strate that DAA infusion accelerates the control of coagulation activation in patients with a D-dimer level higher than 4 mg/L.
Th is phase II exploratory study sponsored by Eli Lilly and Company (Indianapolis, IN, USA) [2] is of special interest because the use of thrombolytic therapy in patients with submassive PE is a matter of signifi cant and ongoing debate [3,4]. Low-molecular-weight heparins (LMWHs) still represent the gold standard for the treatment of venous thromboembolism, as they have proven to be very eff ective and to have a high effi cacy/ safety ratio [5]. Nevertheless, evidence suggests that thrombolytic agents may rapidly dissolve blood clots and might reduce the death rate associated with PE. However, there are concerns about the possible risk of adverse eff ects of these agents, such as life-threatening hemorrhage. Th erefore, another antithrombotic drug could be an attractive alternative.
DAA, a vitamin K-dependent protein, is a potent anticoagulant agent that inhibits activated coagulation factors V and VIII (Va and VIIIa) [6]. Th is mechanism is responsible for a signifi cant reduction in thrombin generation. It also promotes fi brinolysis by inhibiting fi brino lytic inhibitors such as plasminogen activator inhibitor-1 and thrombin-activatable fi brinolysis inhibi tor. Th e global resultant eff ect of DAA on coagulation is more than complex. Dhainaut and colleagues [7] have demonstrated that this compound could be benefi cial in overt and nonovert disseminated intravascular coagu lation patients while partially controlling the activation of the system. Moreover, DAA has been used in managing acute myocardial infarction patients after thrombolysis [8]. As an activation of the coagulation system with a high level of thrombin generation is often observed in (nonseptic) PE patients, combining DAA with an LMWH could be understood as a very interesting hypothesis in this regard, even if the sum of the two parts is not as great as the whole.
Dempfl e and colleagues have compared increasing doses of DAA for a short duration of infusion (12 hours) with placebo in enoxaparin-treated patients. Up to now, little has been known about the endogenous plasma level of activated protein C in (nonseptic) PE patients. Interestingly, the endogenous activated protein C levels were elevated in the DAA-treated group but not in the control group. Th is unexpected fi nding represents the pivotal data of this study, creating the potential for further developments in the fi eld.
Unfortunately, the road to improve our understanding of drugs is not always straightforward. Some hurdles can slow down the development of our projects. Sometimes, physicians use shortcuts to save time, forgetting that pharmacology follows very strict rules. It seems that no

Abstract
Combining therapeutic doses of low-molecularweight heparins and increasing doses of recombinant activated protein C -Drotrecogin alpha (activated), or DAA -is of theoretical interest with regard to the control of coagulation activation. The study by Dempfl e and colleagues presents new data showing that endogenous activated protein C levels do not increase in nonseptic patients with pulmonary embolism. However, the results of the addition of these two treatments are puzzling, leaving unresolved the questionable clinical relevance of this combination and the possible increase in bleeding risk.
animal study and no phase 1 study were performed before the start of the study by Dempfl e and colleagues. Combining a potent anticoagulant (LMWH) with another one (DAA) should have been tested, at least, in healthy volunteers.
Furthermore, if LMWHs have already been given concomitantly with therapeutic doses of DAA in the past [9][10][11], the doses were only prophylactic, and, to our knowledge, no therapeutic doses have ever been combined with DAA in nonseptic patients, and this is because the bleeding risk of these patients is much diff erent than that of hypercoagulable septic patients. As already mentioned, DAA develops an anticoagulant activity. In several pivotal DAA trials in sepsis, some major bleeding episodes have been reported to be related to this anticoagulant eff ect [10,11]. Moreover, in daily clinical practice, the induced-bleeding risk of DAA was reported to be much higher than that of the control trials [12]. In the study by Dumpfl e and colleagues, which is actually registered as a safety study [2], the observed results are a little bit disappointing, leaving unresolved the potentially increased bleeding risk. Th e authors state that DAA accelerates the control of coagulation activation in a subgroup of patients with high levels of intravascular fi brin. Is there any clinical need for that? No signifi cant diff erence is observed in echocardiographic data between the treated group and the control group. Finally, as one patient in the DAA group developed an intracranial hemorrhage (which is fairly uncommon in enoxaparintreated patients), the question of the clinical benefi t of such a combination has to be raised, notwithstanding the low power of this study to detect an increase in major bleeding. Eventually, the debate remains very interesting. DAA is a fascinating compound, and its never-ending story is complex! Abbreviations DAA, Drotrecogin alpha (activated); LMWH, low-molecular-weight heparin; PE, pulmonary embolism.